RT Journal Article
SR Electronic
T1 Development of a Novel in Vitro Model to Predict Hepatic Clearance Using Fresh, Cryopreserved, and Sandwich-Cultured Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1446
OP 1454
DO 10.1124/dmd.30.12.1446
VO 30
IS 12
A1 Yau Yi Lau
A1 Elpida Sapidou
A1 Xiaoming Cui
A1 Ronald E. White
A1 K.-C. Cheng
YR 2002
UL http://dmd.aspetjournals.org/content/30/12/1446.abstract
AB Sixty-four compounds with diverse structures were used in evaluation of intrinsic clearance by various hepatocyte preparations from rats, dogs, monkeys, and humans. Intrinsic clearance (CLint) was calculated from the ratio of the initial amount of the test compound minus the amount remaining after 2 h of incubation and the corresponding area under the concentration versus time curve. The predictive potential of this in vitro model was tested by comparing the intrinsic clearance with in vivo clearance using linear regression analysis. In addition, the intrinsic clearance values obtained from three different types of hepatocytes (cryopreserved, fresh, and sandwich-cultured) from the same species were compared to determine the influence of preservation and culture conditions. It seems that intrinsic clearance determined from human cryopreserved hepatocyte (R2 = 0.87) was the best predictor for the corresponding human in vivo clearance. Dog and rat hepatocyte clearances were also demonstrated to be reasonable predictors (R2 ranged 0.68–0.85 in dogs and 0.65–0.72 in rats) for their corresponding in vivo clearances. Monkey hepatocyte clearance seems to be the worst predictor for the corresponding in vivo clearance (R2 = 0.35–0.67). Comparison of intrinsic clearance generated from cryopreserved and fresh hepatocytes demonstrated a very good correlation in dog (R2 = 0.82) followed by rat (R2 = 0.77), and then by monkey (R2 = 0.70). A similar correlation profile was shown between cryopreserved hepatocytes and sandwich-cultured hepatocytes. These results demonstrated the predictive potential of intrinsic clearance for rat, dog, and human in vivo clearance, but also showed some limitation of the approach for monkey. The American Society for Pharmacology and Experimental Therapeutics